ALS research is at a significant tipping point, and we can now envision a future where ALS becomes a treatable condition.

This was one of the highlights shared by Dr. David Taylor, Vice President of Research at ALS Canada, during a webinar presentation on June 13, 2017. The webinar was the first in a series of four to provide an update on the latest ALS research, clinical trials and funding programs.

In sharing the advances made in ALS research discovery over the years, Dr. Taylor recalled reading an ALS paper in 2001 that was authored by leading neuroscience researcher Dr. Don Cleveland. The paper outlined four likely contributing causes of ALS, but there was clearly still so much not known about the disease. Since then, however, the major discoveries made possible through research in Canada and around the world have led to significant and exciting progress.

During the webinar, Dr. Taylor shared the milestones of major discoveries since the 1940s and discussed exciting recent advances made possible as the pace of discovery has accelerated significantly. Today, many promising gene targets have been identified, there are several potential therapies in clinical trial, and the drug edaravone (Radicava) was recently approved in the U.S.

Here are key highlights from the webinar:

ALS Discovery Milestones

  • 1940s to 1960s: Post-mortem tissue samples and clinical observation were the only tools available for researchers to be able to understand the disease from a biological perspective. By the 1960s, it was discovered that 5 to 10 per cent of ALS cases are familial, meaning they are capable of being passed on from parents to children. The scientific community realized that if the genes involved in familial ALS could be identified, those insights could shed light on the 90 per cent of sporadic cases not linked to a family history.
  • 1980s: Advances in technology meant that for the first time, it was possible to identify genes involved in the development of disease. For the ALS research community, this meant a focused effort on finding genetic mutations linked to ALS, and gene-hunting efforts began in earnest.
  • 1993: SOD1 was the first gene to be identified as playing a major role in the development of ALS, in about one-fifth of familial/hereditary cases. Over the next 13 years, researchers continued to study the SOD1 gene while also trying to identify other genes that might play a role in the development of ALS – these would provide researchers with the tools needed to create animal and cell models of the disease to understand how it is caused at the cellular and molecular level.
  • 2006 to 2011: In 2006, TDP-43 was the second major biological player to be identified as having an important role in the development of ALS. Between 2007 and 2011, scientists discovered several more genes, including C9orf72, linked to ALS.
  • 2012 to 2015: The rate of ALS gene discovery accelerated significantly. By the end of 2015, more than 20 genes had been identified and the list keeps growing today.
  • Today, researchers are studying dozens of identified gene targets alone and in combination to look for common pathways that determine the mechanisms of disease. Avenues of investigation include inflammation, RNA metabolism defects, misfolded protein errors and cell trafficking mistakes.

New Technologies and Big Data

Precision medicine advances mean that it is now possible to study human ALS in a laboratory setting. Using blood samples, scientists can create stem cells, grow them into motor neurons and other important cells relevant to ALS, and then look for differences in biological signatures between people with and without ALS. The technology is expensive, so many organizations are pooling data, resources and findings. In one initiative called Project MinE, ALS Canada is collaborating with organizations in over 17 countries in to map the DNA profiles of more than 15,000 people living with ALS and 7,500 people without ALS. The goal of Project MinE is to identify the “genetic signature” that leads to the development of ALS, in order to be able to target the development of treatments.

Advanced computing platforms that use artificial intelligence and machine learning can process vast amounts of data, such as the data becoming available through Project MinE, and find connections significantly faster than humans can. Researchers in the U.S. recently used IBM Watson Health to sift through information already known up to 2014 about certain aspects of ALS, as a sort of “training test” to see if this form of machine learning could use that knowledge to predict 2015 and 2016 discoveries. When it did, Watson was given all of the information up to 2016 and asked to predict future discoveries. Watson identified five new ALS genes that are currently being validated.

Biomarkers, biological markers in blood or other tissues that indicate the presence of disease or response to treatment, are now known to be critically important for studying ALS: they could help screen people for entry into clinical trials of experimental therapies that are likely to be effective for them, and allow researchers to determine the effectiveness of experimental treatments. While there are currently few biomarkers for ALS, a 2013 Phase 2 trial of the Neuraltus drug NP001 failed to find an effective response across all participants, but on further investigation of the data, a subset of individuals with elevated signs of inflammation showed no disease progression over six months. As a result, a new trial of NP001 is underway where participants are pre-screened for C-reactive protein, a biomarker for inflammation. The identification of biomarkers for ALS will continue to be an important area of exploration.

Clinical Trials

An encouraging number of clinical trials underway are testing new therapies for ALS. In 2016 alone, there were:

  • Many Phase 1/2 studies underway, or on the near horizon. Phase 1/2 studies typically have a small number of participants and their primary purpose is to test safety and determine any adverse side effects.
  • A number of prominent studies in Phase 2 should have results in the near future that will tell us if they move on to Phase 3: Lunasin; Neuraltus’ NP001 (with biomarker); tocilizumab (Actemra); and ezogabine (retigabine). Brainstorm (NurOwn) will be moving to Phase 3 soon.
  • Two impressive Phase 3 trials, which help to determine if the progression of ALS can be slowed:
    • Masitinib (Europe): Results showed a significant therapeutic benefit i for slowing disease progression and drug approvals were filed in Europe with a decision pending. A global clinical trial for masitinib led by a Canadian investigator will open this fall to solidify if this effect is real.
    • Tirasemtiv (VITALITY-ALS): Phase 3 results are expected this summer, following promising results in Phase 2 that showed a reduction in the loss of breathing capacity

Recent FDA Approval of Edaravone (Radicava)

The biggest news in 2017, so far, is the approval of edaravone (Radicava or Radicut) by the United States Food and Drug Administration in May. It’s the second drug to be approved by the FDA for the treatment of ALS: the first drug, riluzole, was approved more than 20 years ago. In clinical trials, edaravone showed a modest but significant slowing of disease progression among participants who were early in their ALS disease progression with mild symptoms and a large vital breathing capacity.

Fueling Future Discoveries

Dr. Taylor is not the only scientist excited about recent progress in ALS research. The same Dr. Cleveland, whose paper Dr. Taylor read back in 2001, recently co-authored a new paper that said, “There is… little doubt that the pace of discovery will continue or even accelerate in several areas of research …most importantly, there will be considerable achievements in the development of therapies for ALS.”

“We now know a wide range of the genetic mutations involved in ALS to study in order to reach the next breakthroughs — but we have more tools than resources or funding to study all of them in a quick and effective way,” said Dr. Taylor. “At ALS Canada, we believe it’s a matter of ‘when’ not ‘if,’ there will be therapies, and that ‘when’ really does depend on funding.”

Future Webinars

Please join us for the next webinars in the series:

All webinars are free, presented online at 12:00 pm Eastern time.

Read about ALS Canada’s Research and consider making a donation today.

Posted in: Research